HIV Rev mediates nuclear export of unspliced and partially spliced HIV mRNA and is a critical regulator of the viral life cycle. Rev shuttles between nucleus and cytoplasm but is predominantly associated with the nucleolus of infected cells. As observed for other nucleolar proteins such as Cdc14 and Mdm2, the reversible association of Rev with the nucleolus appears to be critical to its regulatory function. There is a growing body of evidence suggesting that sensing cellular stress may represent a key function of the nucleolus. Disruption of the nucleolus often accompanies cellular stress and is associated with MDM2 inactivation and modulation of p53 function. We have examined the intranuclear targeting of the Rev protein using a GFP fusion protein composed of full-length Rev and a hormone-responsive element. This chimeric protein allows for control of nuclear import, nucleolar targeting and export of Rev. By modulating the conditions of the in vitro assay, one can distinguish between 1.) the process of nucleolar release and 2.) translocation across the nuclear pore complex. In addition, we have recently demonstrated that the leader peptide of MMTV Env precursor (MMTV-p14) localizes to the nucleoli of murine lymphomas that harbor MMTV. Like Rev, MMTV-p14 contains nuclearnucleolar targeting signals. Furthermore both Rev and MMTV-p14 bind similar cellular targets (B23 and ribosomal protein L5). The sequence of MMTV-p14 is as similar to HIV-rev as is HTLV-rex. Previous work suggests that dominant-negative mutants related to Rev and Rex can provide protective effects and prolong the survival of T cells. Although nucleolar association may represent a common regulatory paradigm, it is likely that the identification of requirements for Rev nucleolar tethering (such as specific kinases) may reveal novel targets for antiviral therapies. The use of a Rev-like peptide such as the leader peptide of MMTV (MMTV-P14) allows the development of HIV protective reagents unrelated to sequences in the HIV genome.